To the Editor:—

In a recent investigation published in Anesthesiology, 1we reported on the effects of activated clotting time–based heparin management (ACT group) compared with a heparin concentration–based anticoagulation strategy (HMS group) on hemostatic activation and inflammatory response during cardiopulmonary bypass (CPB). Results of this investigation revealed that a heparin concentration–based management was associated with higher heparin concentrations and decreased thrombin activation, whereas fibrin generation levels were comparable in the two groups. We assumed that, because of the decreased concentrations of antithrombin during CPB, even the higher concentrations of heparin in the HMS group were less effective in complete attenuation of fibrin formation. However, for inhibition of central upstream coagulation cascades, which finally lead to thrombin activation, heparin action also requires antithrombin. Therefore, a mechanism of heparin action independent of antithrombin must be responsible for the observed differences in thrombin activation in the two groups.

Endothelial release of tissue factor is a central mechanism for the initiation of coagulation. The pivotal role of tissue factor in hemostatic activation during CPB is increasingly appreciated. 2Physiologically, the effect of tissue factor is balanced by tissue factor pathway inhibitor (TFPI). However, the endothelial release of TFPI is a powerful antithrombin-independent anticoagulant effect of heparin. In human plasma, 85–90% of TFPI is bonded to the different lipoprotein factions, and the remaining 10–15%, representing the active antithrombotic fraction, circulates as free TFPI and reduces thrombin activation by inhibition of the tissue factor–FVIIa complex and the protease FXa. Previous investigations 3assessing hemostatic activation during CPB revealed a positive correlation between concentrations of heparin and TFPI and negative correlations between TFPI and tissue factor concentrations. We speculated that the underlying mechanism for the reduced thrombin activation in the HMS group was increased endothelial release of TFPI with subsequent inhibition of the extrinsic coagulation pathway.

In the current study, we analyzed samples obtained during our previous investigation (plasma from citrated whole blood, which was immediately separated and stored at −80°C for a maximum of 3 months) and compared concentrations of free TFPI (TFPIf) and total TFPI (TFPIt) between the ACT and HMS groups. Samples were measured using enzyme-linked immune assays (Asserachrom® Free/Total TFPI; Diagnostica Stago, Asniéres-sur-Seine, France). Statistical analysis was performed using the Student t  test. Data are given in table 1.

Table 1. Concentration of TFPIfand TFPItbefore and after CPB

Table 1. Concentration of TFPIfand TFPItbefore and after CPB
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Table 1. Concentration of TFPIfand TFPItbefore and after CPB
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The administration of high doses of heparin during CPB resulted in a more than 10-fold increase in TFPIfand an approximately 3-fold increase in TFPIt(which is attributed to the strong increase in TFPIf) in both groups. However, unexpectedly, the concentrations of TFPIfwere significantly increased in the ACT group, in which lower heparin concentrations had been measured before. 1Direct effects of heparin may be responsible for these results. However, this observation must be characterized in further studies.

Recently, Kemme et al.  4reported that a continuous infusion of low-dose heparin (2,000 U over 40 min) resulted in a peak of TFPI release (and peak concentrations of TFPIf+tthat were almost comparable with our findings after CPB) after 17 min, indicating fast exhaustion of endothelial TFPI pools even at this low heparin dosage (estimated heparin concentration, 0.2–0.4 U/ml). In our patients, the nearly 10-fold concentrations of heparin (2–3 U/ml) were maintained over a more extended period of time (approximately 80 ± 21 min).

Massive release of TFPI after administration of heparin may present an important mechanism for attenuation of hemostatic activation during CPB. However, considering the long half-life of TFPI (107 min) 5and fast exhaustion of TFPI at low concentrations of heparin, 4the reduced thrombin activation in the HMS group clearly cannot be attributed to a mechanism in which TFPI plays a pivotal role.

1.
Koster A, Fischer T, Praus M, Haberzetl H, Kuebler W, Hetzer R, Kuppe H: Hemostatic activation and inflammatory response during cardiopulmonary bypass: Impact of heparin management. A nesthesiology 2002; 97: 837–41
2.
Chandler W, Velan T Estimating the rate of fibrin and thrombin formation in vivo during cardiopulmonary bypass. Blood 2003; 101: 4355–62
3.
Kojima T; Gando S, Kemmotsu O, Mashio H, Goda Y, Kawahigashi N, Watanabe N: Another point of view on the mechanism of thrombin generation during cardiopulmonary bypass: Role of tissue factor pathway inhibitor. J Cardiothorac Vasc Anesth 2001; 15: 60–4
4.
Kemme MJ, Burggraaf J, Schoemaker RC, Kluft C, Cohen AF: Quantification of heparin-induced TFPI release: A maximum release at low heparin dose. Br J Clin Pharmacol 2002; 54: 627–34
5.
Kamikubo Y, Hamuro T, Matsuda J, Kamei S, Jyu-ri K, Miyamoto S, Funatsu A, Kato H: The clearance of proteoglycan-associated recombinant tissue factor pathway inhibitor (h-r-TFPI) in rabbits: A complex formation of h-r-TFPI with factor Xa promotes a clearance rate of h-r-TFPI. Thromb Res 1996; 83: 161–73